Spinal cord injury (SCI) is a devastating neurologic insult that can disrupt ascending and descending neural circuits necessary for walking, somatosensation, urination and other vital autonomic functions. The majority of SCI patients suffer from anatomically and functionally incomplete spinal cord injury (I-SCI) that results in varying degrees of neurological dysfunction. Although long-distance regeneration of central nervous system (CNS) axons does not occur in mammals, clinical and experimental studies demonstrate considerable spontaneous recovery of neurological function after I-SCI. Experimental studies in rodents and non-human primates indicate that synaptic reorganization between supraspinal motor tracts and spared intraspinal relay circuits that bypass a spinal lesion can re-establish brain-cord communication, and give rise to remarkable motor recovery after I-SCI. Corresponding relay circuit formation may also play a role in motor recovery in hemipalegic stroke patients. Unfortunately, a limited understanding of the cellular and molecular mechanisms governing this functionally meaningful intraspinal circuit plasticity has precluded development of therapeutics to augment this spontaneously occurring recovery process. Astrocytes are critical regulators of synaptogenesis and circuit development during development, and moderate synaptic strength and structural synaptic plasticity following changes in neural activity. In response to diverse CNS injuries, astrocytes undergo graded and regionally distinct changes in structure and function collectively referred to as reactive astrogliosis. After SCI, scar-forming, reactive astrocytes surrounding lesions are indispensible regulators of inflammation. The functions of non-scar-forming, reactive perineuronal astrocytes in spinal cord regions undergoing functionally meaningful circuit remodeling after SCI are not clear, but potential roles include regulation of synapse recovery and neuroprotection. The objective of the current study is to delineate fundamental molecular mechanisms through which astrocytes modulate intraspinal synaptic reorganization and spontaneous locomotor recovery after SCI. In Aim 1, I will use an in vivo, astrocyte-specific transcriptomics approach to delineat key changes in perineuronal astrocyte gene expression that underlie spontaneous locomotor recovery in a mouse model of I-SCI. In Aim 2, I will use neuroanatomical tract tracing, electromyography and in vivo astrocyte-specific genetic manipulations to assess the functional relevance of perineuronal astrocyte reactivity for supraspinal- intraspinal synaptic remodeling and locomotor recovery after I-SCI. Together, these studies will serve as a critical first step towards identifying astrocyte molecular pathways that may be therapeutically targeted to enhance functionally relevant plasticity and promote recovery of neurological function after I-SCI. Such findings are also relevant to patients with traumatic brain injury, stroke or neurodegenerative disease such as multiple sclerosis, in which therapeutically harnessing synaptic plasticity of neural circuitry in spared tissue may be a key to promoting recovery of neurological function.